The liver is the heaviest gland of the body, weighing about 1.4 kg (about 3 lb) in the average adult, and is the second largest organ after the skin. It is almost completely covered by peritoneum and completely covered by a dense irregular connective tissue layer lying beneath the peritoneum. The liver is divided into two principal lobes: a large right lobe and a smaller left lobe. The lobes are separated by the falciform ligament, which is a reflection of the parietal peritoneum. It extends from the undersurface of the diaphragm to the superior surface of the liver, between the two principal lobes of the liver. In the free border of the falciform ligament is the ligamentum teres (round ligament). It extends from the liver to the umbilicus. The ligamentum teres is a fibrous cord that is a remnant of the umbilical vein of the fetus.
The lobes of the liver consist of many functional units called lobules. Each lobule consists of specialized epithelial cells, called hepatocytes (i.e., parenchymal cells), arranged in irregular, branching, interconnected plates around a central vein. Rather than capillaries, the sinusoids, through which blood passes. The sinusoids are partly lined with phagocytes called stellate reticuloendothelial (Kupffer's) cells.
The liver's main function is to control the level of particular substances in the blood. For instance, the liver plays a major role in carbohydrate metabolism by removing glucose from the blood, under the influence of the hormone insulin, and storing it as glycogen. When the level of glucose in the blood falls, the hormone glucagon causes the liver to break down glycogen and release glucose into the blood. The liver also plays an important role in protein metabolism, primarily through deamination of amino acids, as well as the conversion of the resulting toxic ammonia into urea, which can be excreted by the kidneys. The liver also detoxifies many drugs and hormones. In addition, the liver participates in lipid metabolism by storing triglycerides, breaking down fatty acids, and synthesizing lipoproteins. The liver also secretes bile, which helps in the digestion of fats, cholesterol, phospholipids, and lipoproteins. In addition, the liver stores vitamins (A, B.sub.12, D, E, and K) and minerals (iron and copper). Furthermore, the Kupffer's cells of the liver phagocytize worn-out red and white blood cells as well as some bacteria. Bilirubin, a breakdown product of heme, is excreted by the liver into the bile ducts where it passes into the intestinal tract.
There are many different causes of liver disorders. Hepatitis, an inflammation of the liver, is commonly caused by alcoholism or other toxic ingestion, or infection by viruses or other parasites. Cirrhosis of the liver is marked by the destruction of parenchymal cells and their replacement with connective tissue. Hepatitis resulting from infection by hepatitis C virus, for example, often develops into cirrhosis. Hepatitis B virus infection, on the other hand, is strongly believed to lead in many cases to liver cancer (hepatoma). Hepatoma can also be caused by the activation of endogenous oncogenes, through exposure to carcinogens, for example.
Severe forms of these disorders may result in chronic or acute hepatic failure. Fulminant hepatic failure (FHP) is associated with massive necrosis of hepatocytes and concomitant sudden severe impairment of hepatic metabolism. The clinical picture is usually dominated by symptoms of severe attrition of mental functions--a situation which, in most cases, rapidly advances to stupor or coma. An early onset of jaundice is also a characteristic finding and with increments of abnormal enzyme blood levels, these patients usually die within a week. Partial or total liver replacement is needed in case of transient or permanent failure of vital liver functions. Even with recent advances in supportive therapy, patients with FHP still exhibit a mortality rate in excess of 80%.
Unlike other internal organs, the liver has a remarkable capacity to regenerate. In the rat, for example, a 70% hepatectomized liver will regenerate its original mass in about seven days. Nonetheless, because the liver carries out so many important biochemical functions, severe liver damage or loss of the liver is rapidly fatal. Some efforts have been made, therefore, to identify the molecular factors involved in the liver regeneration process.
Most previous studies have focused on events occurring in the first few (e.g., 1-6) hours after surgery. In this regard, Hagiya et al., 1994, Proc. Natl. Acad. Sci. USA 9:8142-8146, cloned ALR (augmenter of liver regeneration) from rat; Hsu et al., 1992, Mol. Cell Biol. 12:4654-4665, identified a gene encoding a novel leucine-zipper containing protein termed liver regeneration factor-1 (LRF-1); and Mohn et al., 1991, Mol. Cell Biol. 11:381-390, identified 41 novel immediate-early partial DNA sequences. These genes were isolated by examining expression during early time periods following partial hepatectomy (e.g., 1-6 hr). During this early stage of regeneration, the expression of acute phase inflammatory proteins is substantially high, thereby yielding a "background" of induced expression of genes which are not very useful because their expression is not specific to liver regeneration. Overcoming this lack of specificity may be a determining factor in obtaining urgently needed tools for early diagnosis of liver disorders, as well as improvements in therapy that take advantage of the liver's unusual regenerative capacity.